Protein kinase C (PKC) related disorders are important causes of illness, disability and death worldwide, and represent important therapeutic targets. The broad range of disorders which are mediated by PKC include, for example, hyperproliferative diseases, immune related disorders, and cognitive disorders among others. There is need for new therapeutic agents which can target PKC to treat patients with these conditions.
Cancer is a major cause of death in the developed countries, with more than 500,000 human fatalities occurring annually in the United States. Cancers are generally the result of the transformation of normal cells into modified cells that proliferate excessively, leading to the formation of abnormal tissues or cell populations. In many cancers, cell proliferation is accompanied by dissemination (metastasis) of malignant cells to other parts of the body, which spawn new cancerous growths. Cancers can significantly impair normal physiological processes, ultimately leading to patient mortality. Cancers have been observed for many different tissue and cell types, with cancers of the lung, breast, and colorectal system accounting for about half of all cases.
Currently, about one-third of cancer patients can be cured by surgical or radiation techniques. However, these approaches are most effective with cancerous lesions that have not yet metastasized to other regions of the body. Chemotherapeutic techniques currently cure another 17% of cancer patients. Combined chemotherapeutic and non-chemotherapeutic protocols can further enhance prospects for full recovery. Even for incurable cancer conditions, therapeutic treatments can be useful to achieve remission or at least extend patient longevity.
Numerous anticancer compounds have been developed over the past several decades. While these compounds comprise many different classes that act by a variety of mechanisms, one general approach has been to block the proliferation of cancerous cells by interfering with cell division. For example, anthracyclines, such as doxorubicin and daunorubicin, have been found to intercalate DNA, blocking DNA and RNA synthesis and causing strand scission by interacting with topoisomerase II. The taxanes, such as Taxol™ and Taxotere™, disrupt mitosis by promoting tubulin polymerization in microtubule assembly. Cis-platin forms interstrand crosslinks in DNA and is effective to kill cells in all stages of the cell cycle. As another example, cyclophosphamide and related alkylating agents contain di-(2-chloroethyl)-amino groups that bind covalently to cellular components such as DNA.
The bryostatins (Formula A) are a family of naturally occurring macrocyclic compounds originally isolated from marine bryozoa. Currently, there are about 20 known natural bryostatins which share three six-membered rings designated A, B and C, and which differ mainly in the nature of their substituents at C7 (ORA) and C20 (RB).

The bryostatins exhibit potent activity against a broad range of human cancer cell lines and provide significant in vivo life extensions in murine xenograft tumor models. Doses that are effective in vivo are extremely low, with activities demonstrated for concentrations as low as 1 μg/kg. Among additional therapeutic responses, the bryostatins have been found to promote the normal growth of bone marrow progenitor cells, provide cellular protection against normally lethal doses of ionizing radiation, and stimulate immune system responses that result in the production of T cells, tumor necrosis factors, interleukins and interferons. Bryostatins are also effective in inducing transformation of chronic lymphocytic leukemia cells to a hairy cell type, increasing the expression of p53 while decreasing the expression of bcl-2 in inducing apoptosis in cancer cells or at least pre-disposing a cell towards apoptosis, and reversing multidrug resistance (MDR).
At the molecular level, bryostatins have been shown to competitively inhibit the binding of plant-derived phorbol esters and endogenous diacyl glycerols to protein kinase C (PKC) at nanomolar to picomolar drug concentrations, and to stimulate comparable kinase activity. Unlike the phorbol esters, however, the bryostatins do not act as tumor promoters. Thus, the bryostatins appear to operate through a mode of action different from, and complementary to, the modes of action of established anticancer agents; such as cisplatin or taxol. Further, their ability to bind PKC and displace phorbol esters, thus providing complex modulatory activity against a number of PKC isoforms, indicate bryostatins' potential for use in therapeutic applications outside of oncology.
Although the bryostatins have been known for some time, their low natural abundance, difficulties in isolation and severely limited availability through total synthesis have impeded efforts to elucidate their mode of action and to advance their clinical development. It is desired to provide new, simplified, and more readily accessible analogs of the natural bryostatins for anticancer applications.